Process for preparing indole compounds



f atented Aug. l9, 1 952 245071779 raocass FOR PREPARING VI-NDOLE COMPOUNDS Edmund B. Towne and Hubert M. Hill, Rochester; N. Y., assignors to Eastman Kodak Company; Rochester, N. Y., a corporation of New Jersey 'No Drawing. Application March 31, Serial No. 153,304

14 Claims.: (01.260-319) -*This invention relates to-a novel andadvantageous process for preparing indole compounds comprising I reacting a N-(2-chloroallyl) -aryl-' aminewith hydrogen fluoride. It is especially directed to a process for preparing indole com-' pounds by reacting a N-(2-chloroally'l)-aniline with hydrogen. fluoride.

It is known to prepare '2-methylindoleby cyclizing acetone phenylhydrazone with ZnClz: (Annalen 236, 126, German Patent 38,784 and Frdl. I. 151). Z-methylindole can also be prepared by the cyclization of Likewise Z-methylindole can be prepared by the cyclization of N-acetyl-o-toluidine with sodium amide (Organic Synthesis 22, 94 [1942]). Of these three known methods for preparing 2- methylindole, the last is probably the best.

The novel process of the present invention provides a more economical method for preparing indole compounds than any of the prior methods of which we are aware since hydrogen fluoride is cheap, the N-(2-chloroal1yl)-arylamines are relatively inexpensive and satisfactory yields are ordinarily obtained. The indole compounds obtained in accordance with our new process are, in large part, old compounds. They are useful, for example, in the preparation of perfumes, dyes, and inhibitors. 7 I

In accordance with the process of our invention, a vN-(2 --chloroallyl)-arylamine in which there is a free position ortho to the 2-chloroallylamino group is heated with hydrogen fluoride. By this treatment the N-(Z-chloroallyD- 'arylamine employed in the reaction is cyclized to an indole compound. The reaction can be carried outat a temperature of from about 120 C. to about 200 C.' At 100 C. little or no reaction takes place; A temperature of 160 C.-170 C. appearsto be advantageous and is preferred.

The. useof'anhydrous hydrogen fluoride is ad chloroallyl) -aniline' to 2-methylindole in accordance with the process of our invention:

So far as we are aware, the N-(2-chloroallyl) arylamine's employed'in the process of our invention l are new. compounds and accordingly their preparation is fully disclosed hereinafter. The process of our invention in addition to being novel and advantageous is also unexpected. Assuming that N-(2-chloroallyl)-aniline would cyclize to an indole compound, the normal expectationwould be to obtain B-methylindole instead of 2-methylindole.

Again-it might'be expected that ifa N-(2- ch1oroallyl)-arylamine such as N-(2-chloroal IyD-aniline .were heated with HF the reactionv would go as follows:

Actually ctmr romorzom is formed in amounts varyin g'from little or none to about a 10% yield while carrying out "the process of our invention.

N-(Z-chloroallyl)-arylamine such as N( 2-ch'lo- In contrast to N-(2-chloroallyl)-aniline the known compound N-(y-0hloroallyl)-aniline I H (CaH N- CHFCHCHzCl) as more fully'set forth hereinafterfldoes."noti cychze to form an indole compound when re-. acted with HF. Instead, a tarry residue and,

some unidentified liquids were obtained.

The product obtained by reacting N-(2-chloroallyl) aniline with HF in accordance with ,7 the process of our invention was identified as-follows: (1) The melting pointof the purified prod not was taken and found to be the same as thatv fora known sample of 2-methy1indo1e, (2) The: melting point of a-mixture of the purified prod-1 Additionally the possibility esisted that if "a product obtained in accordance with the process of our invention with benzaldehyde was taken.

The melting points of both reaction products as well as their mixed meltingpoint were the same.

CCHs 2 H @0110 f 'CH8.:C./ I

ll c The following examples illustrate the process of our invention: 7

' Example I 295 grams of N-(Z-chloroallyD-aniline and 400 grams of anhydrous hydrogen fluoride were charged into a 1 liter shaking autoclave. Shaking was begun and the temperature raised to 140 C. over a 12 hour period and heating was continued for 24. hours more at this temperature. The autoclave was then cooled to 50 C. and the gaseous contents were bled through a dilute,

aqueous sodium hydroxide scrubber. After this the contents of the autoclave were poured onto ice and neutralized with aqueous sodium carbonate. The solid product formed was extracted with benzene from the aqueous suspension and the benzine solution was dried over solid potassium hydroxide. Rectification of the benzene solution yielded a small amount of N-(2-'di'-" reaction mixture was raised to 200 C. and mai n,

tained at this temperature for 16 hours. Upon working up the reaction mixture in the same way as described in Example 1,a yield of 105 grams (67% yield) of z-methylindole was obtained.

By the use of '241 grams of N-(2-chloroallyl) 4-chloroaniline in place of N-(Z-chloroallyD- aniline in the foregoing example, 5-chloro-2- methylindole which melts at 119 C. is obtained.

Eagqmple In" 200 grams of N-(Z-chloroallyl)-m-toluidine and 200 grams of anhydrous hydrogen fluoride were-charged into a 1 liter shaking autoclave. Shaking was begun and the temperature of the reaction mixture was raised to 170? C. and maintained at this temperature for 15 hours. Upon cooling, the gases were vented into an aqueous sodium hydroxide solutionand thecpntents of the autoclave. were poured onto ice :and neutralized with aqueous sodium hydroxide. The oily material was taken up in benzene and dried over KOI-I. Rectification of the benzene extract gave '77 grams of a mixture of 2,4-dimethylindole and 2,6-dimethylindole; B. P. 140-145 C./5

mm. This is a 48% yield.

Y g Example IV 358 grams of N-(Z-chloroallyl)-1-naphthylamine and 300 grams of anhydrous hydrogen fluoride were sealed in a 1 liter autoclave. Shaking was begun and the temperature of the reaction mixture was raised to 180 C. and maintain d at this. temp rature. is: 16.110. .25.- Iln n coolin to C. the ases were vented: intq an aqueous sodium hydroxide sqlut-ion and the, Q0111..- tents of the. autoclave were poured-onto. iceand neutralized with aqueous sodium hydroxide. The crude solid product formed was recovered by filtration. It gave a positive indole pine. splint test. The solid reaction. product. was extracted with benzene in a Soxhlet extractor for 24 hours. Upon evaporation .ofthe. benzene extract Z-methyl-Gfl-benzodndole melting atv 132 .C.. wa's obtained. It has the. formula: c

Similarly, by the use of Nr"(,2 i-chloroallyli),.-j2- naphthylarnine in place of .N(2'-lchloroal 1) 11,-.

naphthylamin in t e f re o n example;

2 methy1-4,5benzoiindole boiling t, 2.05? cg. 7 2109 one 'mm..i s obtained. It} has the formula:

200 grams of N-(y-ehlorciallyl),:anilineandfi oof grams of a ou H recharg d into liter shaking autoclave. Shaking was begun and, the. temperature of the reaction mixture was raised to about 136 .C. and maintained at. this. temperature for 36, hours. The autoclave, was then cooled and thegaseous.contentswerevented into a dilute aqueous {sodium hydroxide solution After this. the contentsof the a oclaye' were poured onto ice and, neutraliz with, aquepjis, sodium hydroxide- The. reaction mixturelth obtained was steam: distilled,- to. obtain a 'acti n; weighing about 25.-.-30.g1:ams, "Upon re 9n} of this material three unidentified.fractionsw 1;, obtained. Each of thesel fractions gave a neg tive test when tested for thelpresence of an indole compound. The residue, 117 grams, from the steam distillation was an asphalt-like mass..

It will be understood that the foregoing examples are intended to be illustrative and not limitative of the process of our invention. To illustrate, the manner in which the autoclave is vented formsno part of our invention. The gaseous contents could be ventedinto water, an

l e solution .o h itfiana ueo s. s i m .hy-

. Other indo1e. compounds,,in additiongtothose given in the specific examples, which can be .readilyprepared in accordance withthe, process of our invention include those listed hereinafter:

The N -(2-chloroallyl)"-arylamiiie compounds used in the process of our invention are ordinarily prepared by reacting a primary arylamine with 2,3-dichloropropene at steam-bath temperature in the presence of aqueous sodium car-. bonate. The reaction can also be carried out in the presence of a nonaqueous inert solvent such as ethyl alcohol, isopropyl alcohol, n-butyl alcohol. n-amyl alcohol, acetone, benzene, toluene, xylene and the like. Also, as will be understood, acid binding agents other than sodium carbonate such as sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium oxide and calcium carbonate, for example, can be used. Higher boiling solvents such as n-amyl alcohol or xylene are especially useful when the reaction between the aniline compound (o-chloroaniline and o-nitroaniline, for example) and 2, -dichloropropane goes slowly with aqueous sodium carbonate at steam-bath temperature. Thus, the temperature range can preferably vary from 100 C. to about 150 C., depending on the primary arylamine being reacted. In general, the N-(2-chloroallyl) -arylamine compounds are colorless to straw-colored liquids with an odor simliar to but fainter than aniline.

The preparation of the N-(2-chloroallyl)- arylamine compounds will be clear from the detailed examples which follow.

Example VI A mixture of 333 grams of 2,3-dichloropropene, 279 grams of aniline, 175 grams of sodium carbonate and 500 cc. of Water was heated on a steam bath with stirring for '7 hours. After cooling, the organic layer was separated from the water layer and dried over KOH. Upon fractionation under reduced pressure, 378 grams (75% yield) of N-(2-chloroallyD-aniline boiling at 109 C./5 mm. were obtained.

Example VI] A mixture of 222 grams of 2,3-dichloropropene, 214 grams of m-toluidine, 117 grams of NazCO: and, 600 cc. of water was heated on a steam bath with stirring for 6 hours. Upon cooling, the organic layer was separated from the water layer and dried over KOH. Upon fractionation under reduced pressure, 245 grams (67.5% yield) of N-(2-chloroallyl) -m-toluidine boiling at 122 C./5 mm. were obtained.

Example VIII A mixture of 286 grams of a-naphthylamine, 250 grams of 2,3-dichloropropene, 117 grams of NazCOz and 500 cc. of water was heated on a steam bath with stirring for 20 hours. Upon cooling, the organic layer was separated from the water layer and dried over KOH. Upon ivacuum distillation, 358 grams v(82.5 972; yield) of 'N- (2-ch loroallyl) -a-naphthylamine boiling the following compounds are readily prepared:

N-(z-chloroallyl) -o-to1uidine, N-(2-chloroallyl) p toluidine, N-(2-chloroallyl) -0-chloroaniline, N'- 2-chloroa11yl)-m-chloroaniline, N-(2-chloroally1).-pchloroaniline, I N- (2-chloroallyl) -o-nitro eaniline, N- (2-chloroallyl) m-ni-troaniline, N- (2- chloroallyl) -p-nitroaniline, N- (z-chloroallyl). ,-p ph ny n d m n r; -N-. 2-. oa y1) -Q: eny1- enediamine, N 2 -chlor oallyl)emephenylenedia- ,mine, N- (2-chloroallyl) -,3-naphthylamine, N- (2- chloroallyl) -p-aminophenol, N 2-chloroally1).- p-aminobenzoic acid, N-(2-chloroallyD-o-sula ll a claim: f

1. A'process for preparing indole compounds which comprises heating a N-(2-chloroallyl)- arylamine compound in which there is a free position ortho to the 2-chloroallylamino group with hydrogen fluoride in a closed reaction vessel at a temperature from about C. to about 200 C.

2. A process for preparing indole compounds which comprises heatng a N-(2-ch1oroally1)- arylamine compound in which there is a free position ortho to the 2-chloroallylamino group with anhydrous hydrogen fluoride in a closed reaction vessel at a temperature from about C. to about C.

3. A process for preparing indole compounds which comprises heating a N-(2-chloroallyD- arylamine compound in which there is a free position ortho to the 2-chloroallylamino group with anhydrous hydrogen fluoride in a closed reaction vessel at a temperature from about 120 C. to about 200 C.

4. A process for preparing indole compounds which comprises heating a N-(2-chloroallyl)- aniline compound in which there is a free position ortho to the z-chlorallylamino group with hydrogen fluoride in a closed reaction vessel at a temperature from about 120 C. to about 200 C.

5. A process for preparing indole compounds which comprises heating a N-(2-chloroallyl)- aniline compound in which there is a free position ortho to the 2-chloroallylamino group with anhydrous hydrogen fluoride in a closed reaction vessel at a temperature from about 160 C. to about 170 C.

6. A process for preparing indole compounds which comprises heating a N-(2-chloroallyl)- aniline compound in which there is a free position ortho to the 2-chloroallylamino group with anhydrous hydrogen fluoride in a closed reaction vessel at a temperature from about 120 C. to about 200 C. Y

7. A process for preparing Z-methylindole which comprises heating N-(2-chloroally1)- aniline with hydrogen fluoride in a closed reaction vessel at a temperature from about 120 C. to about 200 C.

8. A process for preparing 2-methylindole which comprises heating N- (2-chloroallyl) ani-r line with anhydrous hydrogen fluoride in a. closed reaction vessel at a temperature from about 160 C. to 170 C.

0. A process for preparing 2-methylindole which comprises heating N-(2-chloroallyl)-aniline with anhydrous hydrogen fluoride in a closed reaction vessel at a temperature from about 120 C. to about 200 C.

.12. The process which comprises heating- 'N- '(Z flhlfli'QQillfl) -g-naphthylamine I with anhydrous hydrogen -fiuoride in a'closed reaction vessel at a temperature from about 120 C. to about 200 C. 1

13. The process which comprises heating N- (2-ch1oroa11y1)-B-naphthy1amine .w ith anhy- "arous -hydrogenfiuoridef i-n a -o1 o'sed reaction '14. The process which comprises heating N- (2-ohloroa11y1) -'o-nitroani1ine with anhydrous hydrogen fluoride in a closed reaction vesselat a temperature from about 120 C. to about EDMUND B. TOWNE. HUBERT M.

REFERENCES CITED The following-references are of record in the V file of this patent: r or V Richter: Organic Chemistry, vol. 4, p. 229, E s e ier Publish ng Co- 947).- 

1. A PROCESS FOR PREPARING INDOLE COMPOUNDS WHICH COMPRISES HEATING A N-(2-CHLOROALLYL)ARYLAMINE COMPOUND IN WHICH THERE IS A FREE POSITION ORTHO TO THE 2-CHLOROALLYLAMINO GROUP WITH HYDROGEN FLUORIDE IN A CLOSED REACTION VESSEL AT A TEMPERATURE FROM ABOUT 120* C. TO ABOUT 200* C. 